Trastuzumab-induced Cardiotoxicity Research Articles

HER2/neu 655 polymorphism, trastuzumab-induced cardiotoxicity, and survival in HER2-positive breast cancer patients.

HER2 overexpression in breast cancer correlates with poor outcomes. The incorporation of Trastuzumab into the treatment regimen has notably improved patient prognoses. However, cardiotoxicity emerges in approximately 20% of patients treated with the drug. This study aims to investigate the association between the HER2 655 A > G polymorphism, Trastuzumab-induced cardiotoxicity, and patient survival. The study involved 88 patients treated with Trastuzumab. Cardiotoxicity, defined as a reduction in left ventricular ejection fraction (LVEF) from baseline or the emergence of clinical signs of congestive heart failure, was identified during treatment follow-up. Genotyping of HER2 655 A > G employed TaqMan SNP technology. Genotype frequencies of HER2/neu 655 (53 AA, 32 AG, and 3 GG) were consistent with Hardy-Weinberg equilibrium. No significant differences were observed in mean baseline LVEF between patients who developed cardiotoxicity and those who did not. Within these groups, neither AA nor AG genotypes showed an association with changes in mean baseline or reduced LVEF levels. Logistic regression analysis, adjusted for hormonal status and anthracycline treatment, revealed that AG genotype carriers face a significantly higher risk of cardiotoxicity compared to AA carriers (OR = 4.42; p = 0.037). No association was found between the HER2/neu 655 A > G polymorphism and disease-free or overall survival, regardless of whether the data was adjusted for stage or not. HER2 655 A > G polymorphism is significantly linked to an increased risk of Trastuzumab-induced cardiotoxicity but does not correlate with variations in disease-free survival or overall survival rates.

Abstract PO3-09-02: Identifying risk factors for trastuzumab-induced cardiotoxicity among multi-ethnic women with HER2-positive early-stage breast cancer

Abstract Introduction: While trastuzumab, a HER2-targeted therapy for patients with HER2-positive breast cancer, has been shown to improve disease-free and overall survival rates, it also confers the risk of significant morbidity in the way of trastuzumab-induced cardiotoxicity (TIC). TIC may present as asymptomatic decline in left ventricular ejection fraction (LVEF) or as symptomatic heart failure. Given that racial/ethnic minorities are at higher risk for cardiovascular disease (CVD) compared to non-Hispanic Whites, our objective was to assess racial/ethnic differences in TIC and LVEF recovery among multi-ethnic patients with HER2-positive early-stage breast cancer. Methods: We conducted a retrospective cohort study including patients diagnosed with stage I-III HER2-positive breast cancer between 2007-2022 who had received adjuvant trastuzumab therapy at Columbia University Irving Medical Center (CUIMC) in New York, NY. TIC was defined as >10% decrease in LVEF to an overall LVEF< 50% and was confirmed by a minimum of two serial echocardiograms, whereas LVEF recovery was defined as a return to a LVEF >50%. Descriptive statistics, univariate and multivariate logistic regression analyses were conducted to estimate odds ratios (OR) and 95% confidence intervals (CI) for the associations between sociodemographic factors, tumor characteristics, treatment regimens, and CVD risk factors with the main outcome of TIC. Results: In the final cohort (N=500), median age was 53 years (IQR: 45.0-62.0) with 36.6% non-Hispanic White (NHW), 15.8% non-Hispanic Black (NHB), 27.8% Hispanic, and 19.8% Asian/Pacific Islander/Other. About 68.2% of patients received adjuvant radiation therapy, 30.2% were treated with anthracyclines, 37.8% with pertuzumab, 4.6% with T-DM1 and 69.0% with endocrine therapy. Fifty-three (10.6%) patients developed TIC, half of which experienced LVEF recovery. Compared to NHW, NHB patients had a higher rate of TIC (9.3% vs. 17.7%, respectively) and lower rate of LVEF recovery (70.6% vs. 21.4 % in those with TIC, respectively). On multivariable analysis, increasing age, lower LVEF at baseline, anthracycline exposure, and coronary artery disease (CAD) were associated with TIC (see Table). We found no association between TIC and use of pertuzumab or T-DM1. Discussion: In our racially/ethnically diverse study population, we found an incidence of TIC comparable to previous clinical studies. NHB patients had double the incidence of TIC and a lower incidence of LVEF recovery when compared to NHW patients. Given the observed racial disparities in TIC and LVEF recovery, NHB patients may require closer cardiac monitoring and restricted use of anthracyclines with adjuvant trastuzumab treatment. More research on cardiotoxicity associated with newer forms of HER2-targeted therapies is necessary. Table: Multivariable logistic regression model with outcome of TIC Citation Format: Leila Mishalani, Anna Vaynrub, Katherine Crew. Identifying risk factors for trastuzumab-induced cardiotoxicity among multi-ethnic women with HER2-positive early-stage breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-09-02.

Role of Early Left Atrial Functional Decline in Predicting Cardiotoxicity in HER2 Positive Breast Cancer Patients Treated With Trastuzumab

Trastuzumab is widely used in HER2 breast cancer. However, it may cause left ventricular (LV) dysfunction. A decrease in LV global longitudinal strain (GLS) has been previously demonstrated to be a good predictor of subsequent cancer therapy related dysfunction (CTRCD). Left atrial morphological remodeling during Trastuzumab therapy has also been shown. The aim of this study is exploring the relationship between early changes in left atrial function and the development of Trastuzumab-induced cardiotoxicity. Consecutive patients with diagnosis of HER2+non-metastatic breast cancer treated with Trastuzumab were prospectively enrolled. A clinical, conventional, and advanced echocardiographic assessment was performed at baseline and every three months, until a one-year follow-up was reached. One-hundred-sixteen patients completed the 12 months follow-up, 10 (9%) cases of CTRCD were observed, all after the sixth month. GLS and LVEF significantly decreased in the CTRCD group at 6 months of follow-up, with an earlier (3 months) significant worsening in left atrial morpho-functional parameters. Systolic blood pressure, early peak atrial longitudinal strain (PALS), peak atrial contraction (PACS) and left atrial volume (LAVI) changes resulted independent predictors of CTRCD at multivariable logistic regression analysis. Moreover, early changes in PALS and PACS resulted good predictors of CTRCD development (AUC 0.85; p = 0.008, p < 0.001 and 0.77; p = 0.008, respectively). This prospective study emphasizes that the decline in PALS and PACS among trastuzumab-treated patients could possibly increase the accuracy in identifying future CTRCD in non-metastatic HER2 breast cancer cases, adding predictive value to conventional echocardiographic assessment.

Targeting Cardiomyocytes with Adeno Associated Viruses to Protect Hearts from Trastuzumab-induced Cardiotoxicity

Amplification of HER2 occurs in 20% of breast cancers. HER2 (known as ErbB2 in mouse) belongs to the Epidermal Growth Factor Receptor (EGFR) family that is responsible for cell growth and survival. While HER2 does not bind ligands, it forms heterodimers with HER1 (also known as EGFR) in the presence of its ligand EGF, and HER4 following stimulation with Neuregulin. In HER2-positive breast cancer where HER2 expression is high, HER2 homodimerizes leading to excessive activation of downstream signalling and cell proliferation. Current HER2-positive breast cancer treatment involves chemotherapy with drugs called anthracyclines, such as Doxorubicin, and an antibody targeting HER2 called Trastuzumab. This combination is effective in killing HER2-positive breast tumours, however, Trastuzumab alone or in combination with anthracyclines leads to severe cardiotoxicity and heart failure in 2.6-11% of cases, making it a dose-limiting side effect. We hypothesise that cardiac toxicity can be mitigated by targeting cardiomyocytes exclusively to express a mutated (but functional) version of HER2 that is not recognised by trastuzumab. We designed 3 HER2 variants wherein the trastuzumab binding domain was mutated to disrupt binding. These HER2 mutants were transfected into HEK293T cells, and we confirmed that all 3 successfully localised to the cell membrane, and did not bind trastuzumab. We have used bioluminescence resonance energy transfer to examine the capacity of all 3 mutants to activate recruitment of Grb2 to the HER2 as part of HER1/HER2 and HER4/HER2 heterodimers; Western blotting also confirming mutants were capable of stimulating ERK and Akt phosphorylation. Future studies will evaluate the effcacy of using AAVs to instruct cardiomyocytes to express these HER2 mutants in a murine model of breast cancer. We predict that this new therapy would not only mitigate cardiac toxicity, but would also permit higher doses of trastuzumab to be used to treat breast cancer. This work is supported by Australia's National Health and Medical Research Council and the Australian Research Council. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Trastuzumab-Induced Cardiotoxicity: When and How Much Should We Worry?

This review critically analyzes the incidence of trastuzumab-induced left ventricular systolic dysfunction and congestive heart failure (CHF), distinguishing between cases with and without prior anthracycline exposure. It highlights the fact that the elevated risk of trastuzumab-induced cardiotoxicity is closely associated with prior anthracycline exposure. In the absence of prior anthracycline exposure, the incidence rates of trastuzumab-induced cardiotoxicity, particularly CHF (ranging from 0% to 0.5%), are largely comparable with those reported in the general population, especially when reversibility is taken into account. Current cardiac surveillance recommendations during trastuzumab treatment have not yet adapted to the increasing adoption of nonanthracycline treatment strategies and the associated low risk of cardiotoxicity. We propose a refined monitoring protocol to reduce the frequency of cardiac evaluations for low-risk to moderate-risk patients, especially those receiving nonanthracycline treatments. By focusing on patients at high risk or those with prior anthracycline exposure, this strategy seeks to optimize the cost-effectiveness of cardiac care in oncology.

Identification of ADME genes polymorphic variants linked to trastuzumab-induced cardiotoxicity in breast cancer patients: Case series of mono-institutional experience

BackgroundLong-term survival induced by anticancer treatments discloses emerging frailty among breast cancer (BC) survivors. Trastuzumab-induced cardiotoxicity (TIC) is reported in at least 5% of HER2+BC patients. However, TIC mechanism remains unclear and predictive genetic biomarkers are still lacking. Interaction between systemic inflammation, cytokine release and ADME genes in cancer patients might contribute to explain mechanisms underlying individual susceptibility to TIC and drug response variability. We present a single institution case series to investigate the potential role of genetic variants in ADME genes in HER2+BC patients TIC experienced. MethodsWe selected data related to 40 HER2+ BC patients undergone to DMET genotyping of ADME constitutive variant profiling, with the aim to prospectively explore their potential role in developing TIC. Only 3 patients (“case series”), who experienced TIC, were compared to 37 “control group” matched patients cardiotoxicity-sparing. All patients underwent to left ventricular ejection fraction (LVEF) evaluation at diagnosis and during anti-HER2 therapy. Each single probe was clustered to detect SNPs related to cardiotoxicity. ResultsIn this retrospective analysis, our 3 cases were homogeneous in terms of clinical-pathological characteristics, trastuzumab-based treatment and LVEF decline. We identified 9 polymorphic variants in 8 ADME genes (UGT1A1, UGT1A6, UGT1A7, UGT2B15, SLC22A1, CYP3A5, ABCC4, CYP2D6) potentially associated with TIC. ConclusionReal-world TIC incidence is higher compared to randomized clinical trials and biomarkers with potential predictive value aren’t available. Our preliminary data, as proof of concept, could suggest a predictive role of pharmacogenomic approach in the identification of cardiotoxicity risk biomarkers for anti-HER2 treatment.

Noncoding RNA-associated competing endogenous RNA networks in trastuzumab-induced cardiotoxicity

Trastuzumab-induced cardiotoxicity (TIC) is a common and serious disease with abnormal cardiac function. Accumulating evidence has indicated certain non-coding RNAs (ncRNAs), functioning as competing endogenous RNAs (ceRNAs), impacting the progression of cardiovascular diseases. Nonetheless, the specific involvement of ncRNA-mediated ceRNA regulatory mechanisms in TIC remains elusive. The present research aims to comprehensively investigate changes in the expressions of all ncRNA using whole-transcriptome RNA sequencing. The sequencing analysis unveiled significant dysregulation, identifying a total of 43 circular RNAs (circRNAs), 270 long noncoding RNAs (lncRNAs), 12 microRNAs (miRNAs), and 4131 mRNAs in trastuzumab-treated mouse hearts. Subsequently, circRNA-based ceRNA networks consisting of 82 nodes and 91 edges, as well as lncRNA-based ceRNA networks comprising 111 nodes and 112 edges, were constructed. Using the CytoNCA plugin, pivotal genes—miR-31-5p and miR-644-5p—were identified within these networks, exhibiting potential relevance in TIC treatment. Additionally, KEGG and GO analyses were conducted to explore the functional pathways associated with the genes within the ceRNA networks. The outcomes of the predicted ceRNAs and bioinformatics analyses elucidated the plausible involvement of ncRNAs in TIC pathogenesis. This insight contributes to a better understanding of underlying mechanisms and aids in identifying promising targets for effective prevention and treatment strategies.

Anti-apoptotic and antioxidant mechanisms may underlie the abrogative potential of Ocimum gratissimum Linn. Leaf extract and fractions against trastuzumab-induced cardiotoxicity in Wistar rats

Clinical use of trastuzumab (TZM), has been widely associated with increased incidence of cardiotoxicity. Ocimum gratissimum Linn. is a household medicinal plant popularly used for treating inflammatory conditions. In this study, we investigated the abrogative potential of 100 mg/kg/day of the ethanol leaf extract of Ocimum gratissimum Linn. (OG) and its petroleum ether (PEOG), ethyl acetate (EAOG) and ethanol (EOG) fractions in TZM intoxicated Wistar rats for 7 days using anthropometric, biochemical, histopathological and immunohistochemical endpoints. In addition, secondary metabolite constituents in OG and its fractions were determined through Gas Chromatography-Mass Spectrometry (GC-MS). The study results showed that oral pretreatments with OG and OG fractions as well as the fixed dose valsartan-lisinopril (VAL-LSP) combination effectively ameliorated and restore nearly normal levels the TZM-altered plasma cardiac troponin I and antioxidant profile which were corroborated by histopathological and immunohistochemical findings as indicated by the inhibition of TZM-induced activation of caspases-3 and − 9 and profound upregulation of BCL-2 expression. Phytoscan of OG and its fractions showed the presence of thymol and in high amount. Overall, our findings revealed the cardioprotective potentials of OG, OG fractions and fixed dose VAL-LSP combination against TZM-induced cardiotoxicity which probably was mediated via abrogation of cardiomyocyte apoptosis and antioxidant mechanisms.

HER2-Targeted Therapy-From Pathophysiology to Clinical Manifestation: A Narrative Review.

Trastuzumab is the primary treatment for all stages of HER2-overexpressing breast cancer in patients. Though discovered over 20 years ago, trastuzumab-induced cardiotoxicity (TIC) remains a research topic in cardio-oncology. This review explores the pathophysiological basis of TIC and its clinical manifestations. Their understanding is paramount for early detection and cardioprotective treatment. Trastuzumab renders cardiomyocytes susceptible by inhibiting the cardioprotective NRG-1/HER2/HER4 signaling pathway. The drug acts on HER2-receptor-expressing cardiomyocytes, endothelium, and cardiac progenitor cells (see the Graphical Abstract). The activation of immune cells, fibroblasts, inflammation, and neurohormonal systems all contribute to the evolution of TIC. A substantial amount of research demonstrates that trastuzumab induces overt and subclinical left ventricular (LV) systolic failure. Data suggest the development of right ventricular damage, LV diastolic dysfunction, and heart failure with preserved ejection fraction. Further research is needed to define a chronological sequence of cardiac impairments to guide the proper timing of cardioprotection implementation.

Assessing Adherence to Cardiac Monitoring Guidelines in Trastuzumab-Treated Breast Cancer Patients: Insights From a Tertiary Hospital.

Breast cancer is a global health concern, with a significant portion of patients exhibiting human epidermal growth factor receptor 2 (HER2) overexpression. Trastuzumab is one of the pivotal therapiesfor HER2-positive breast cancer, but it carries the risk of cardiotoxicity. Guidelines for cardiac monitoring are essential to detect early signs of cardiotoxicity. However, adherence to these guidelines remains uncertain. In this single-center retrospective cohort study, we analyzed data from 167 female patients diagnosed with HER2-positive breast cancer who were treated with trastuzumab. We meticulously assessed the level of adherence to cardiac monitoring guidelines and determined the incidence of trastuzumab-induced cardiotoxicity (TIC). Factors affecting adherence were subsequently investigated using appropriate statistical methods. Adherence to monitoring guidelines was only 31.7%. TIC incidence was 7.8%. Patients with concurrent use of cardiotoxic medications demonstrated higher adherence. A significant association was found between the number of trastuzumab doses and adherence. Adherence to monitoring guidelines was suboptimal. Those at a higher risk of cardiac issues showed greater adherence. Improved risk assessment methods are needed to individualize monitoring and intervention. Future research should focus on patient-centered, evidence-based monitoring to optimize the balance between cancer therapy and cardiac safety in the field of cardio-oncology.

Mitochondrial function and oxidative stress in isolated peripheral blood mononuclear cells and trastuzumab-induced cardiotoxicity: a prospective longitudinal study

Abstract Introduction Trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2), is believed to cause cardiotoxicity through mitochondrial dysfunction and oxidative stress. Although peripheral blood mononuclear cells (PBMCs) could represent systemic oxidative stress, they are also involved in trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity. The usefulness of isolated PBMCs in the assessment of trastuzumab-induced cardiotoxicity remains uncertain. Purpose We aimed to determine the temporal changes of mitochondrial function and oxidative stress in isolated PBMCs, and cardiac function in breast cancer patients receiving sequential doxorubin and trastuzumab treatment. Methods Fourteen HER-2 positive breast cancer patients with apparently normal cardiac function at baseline were recruited from September 1, 2020 to August 31, 2022. After breast surgery, all patients received doxorubicin (60 mg/m²) and cyclophosphamide (600 mg/m²) every 3 weeks for 4 cycles, followed by trastuzumab (8 mg/kg loading then 6 mg/kg) every 3 weeks for 18 cycles. Adjuvant paclitaxel (175 mg/m²) every 3 weeks for 4 cycles was an additional treatment in patients with positive lymph node(s). Echocardiography and blood samples were collected at baseline, cycle 4 of doxorubicin chemotherapy, every 3 months during trastuzumab treatment and &amp;gt;1 month after treatment. Seahorse extracellular flux analyzer was used to determine mitochondrial oxygen consumption, and MitoSox/MitoTracker staining to determine oxidative stress in isolated PBMCs. Results Of 14 patients (mean age of 50.4 ±8.8 years), 2 had hypertension and 4 had hyperlipidemia. The serum troponin I levels were significantly increased during doxorubicin treatment, then gradually decreased afterward, while the serum NT-proBNP levels remained statistically unchanged (Figure 1A and B). The numerical reduction of ejection fraction was remarked during the treatment, however there was no clinical cardiac dysfunction (Figure 1C). Subclinical cardiac dysfunction, defined as a &amp;gt;15% relative reduction in global longitudinal strain (GLS), was observed in 9 of 14 patients during trastuzumab treatment (Figure 1D). Mitochondrial oxidative stress in isolated PBMCs, although unchanged during doxorubicin treatment, was gradually increased during trastuzumab treatment (Figure 2A and B). Mitochondrial proton leak was also increased, while oxygen consumption and ATP production remained unchanged (Figure 2C and D). After treatment completion, cardiac function, as well as mitochondrial oxidative stress, tended to improve. Interestingly, there was a strong positive correlation between mitochondrial oxidative stress at baseline and maximum GLS reduction during treatment (r=0.811, p=0.001). Conclusions Mitochondrial oxidative stress in isolated PBMCs could be a potential marker for the evaluation and prediction of trastuzumab-induced cardiotoxicity. Further studies are warranted.Figure 1Figure 2

The potentially protective effect of dapagliflozin on the development of cardiotoxicity in cancer patients

Abstract Introduction The clinical trial "DECLARE-TIMI 58" (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58), demonstrated that dapagliflozin, a Sodium glucose cotransporter 2 inhibitor, reduces the composite end point of cardiovascular death/hospitalization for heart failure in a broad population of patients with type 2 diabetes mellitus.Chemotherapy is known for its potetial adverse effects on myocardium.We hypothesized that early initiation of treatment with dapagliflozin could prevent cardiotoxicity . Purpose We aimed to study if dapagliflozin could exert cardioprotective effects in anthracycline,carfilzomib and trastuzumab-induced cardiotoxicity through the analysis of ejection fraction, global longitudinal strain (GLS) of both left and right ventricle. Methods 32 diabetic patients who were diagnosed with cancer at our medical center were randomized (16 dapagliflozin;16 placebo). The groups were well-matched for baseline characteristics (age, diabetes duration, HbA1c, renal and heart function). Our patients, receiving potentially cardiotoxic treatment: 52% were treated with only trastuzumab, 34% were treated with only anthracycline and 14% with carfilzomib. The primary endpoint was the development of cardiotoxicity after treatment with chemotherapy. Cardiotoxicity was defined as a decrease of LVEF by 5% or more to less than 55% in the presence of symptoms of heart failure or an asymptomatic decrease in LVEF by 10% or more to less than 55%. Results In the first trimester of observation compared to baseline, patients treated with dapagliflozin did not show a deterioration of LV GLS [(GLS = −20,2±3,1% vs −19,8±3,1%, p=0,551] .Similarly in the placebo group [(GLS= −23,02±3,6% vs −22,6±3,5%, p=0,572). No significant changes were found in LVEF after treatment with dapagliflozin (57,9±5,6% vs 57,6±6,1%, p=0,733) or the placebo (60,1±5,6% vs 57,8±6,6%, p=0,166).There was a trend in GLS reduction of left ventricle in 2 patients receiving carfilzomib treatment in the placebo group (p=0.058) Conclusions At the best of our knowledge, our study is the first to investigate the early prophylactic use of dapagiflozin in the development of non-ischemic cardiomyopathy in patients receiving anthracycline or trastuzumab,carflilzomib therapies. During the first trimester of observation there was no benefit by dapagliflozin administration but 2 of our patients in the placebo group demonstrated reduction in GLS of left ventricle.

Upregulation of mitochondrial fusion as potential cardioprotective strategies against trastuzumab-induced cardiotoxicity in rats

Abstract Background Trastuzumab (TRZ) is a commonly used chemotherapeutic drug for treating advanced malignancies that express human epidermal growth factor receptor type 2. However, TRZ has been linked with cardiotoxicity, which is an unfavourable clinical side effect of cancer treatment. Alterations in mitochondrial dynamic mechanisms, particularly reduced fusion, have been shown to be a key mechanistic insight into the progression of chemotherapy-induced cardiotoxicity. Despite the cardioprotective benefits of a mitochondrial fusion promoter (M1) that have been established in various cardiovascular settings, its ability to counteract the cardiotoxicity caused by TRZ remains unknown. Purpose To examine the effect of M1 treatment on mitochondrial fusion, myocardial oxidative stress, apoptosis, and cardiac injury biomarker in TRZ-induced cardiotoxicity rats. Methods Male Wistar rats (n=18) were divided into the TRZ group (4 mg/kg/day for 7 days, I.P., n=12) and the control group (CON, n=6). In the TRZ group, at the time of first TRZ injection all rats also received the intervention with either the vehicle injection (VEH, n=6) or M1 (M1, 2 mg/kg/day, n=6) via I.P. injection for 7 days. The left ventricular ejection fraction (LVEF) was measured using echocardiography, and troponin-I levels were determined using blood serum. Then, the cardiac tissue was processed to assess the levels of malondialdehyde (MDA) for oxidative stress, mitochondrial fusion, and apoptotic proteins. Results TRZ induced cardiotoxicity via downregulation of mitochondrial fusion along with upregulation of myocardial oxidative stress and apoptosis, as indicated by decreasing Mfn1 protein expression and increasing the levels of MDA and Bax to Bcl-2 ratio, respectively (Fig. 1A, B, C, and E). TRZ also showed markedly higher levels of serum Troponin-I (Fig. 1D) and impaired LV function (77% LVEF for TRZ vs. 89% LVEF for CON). M1 co-treatment promoted Mfn1-mediated mitochondrial fusion, resulting in a reduction in MDA-associated oxidative stress, apoptosis, Troponin-I, and cardiac dysfunction (16% improvement over the TRZ group) (Fig. 1A-E). Conclusion M1 effectively protected the heart against TRZ-induced cardiotoxicity by promoting mitochondrial fusion and preventing oxidative stress and apoptosis-mediated myocardial injury. These findings suggest that the pharmacological promotion of mitochondrial fusion could be a novel anti-cardiotoxicity strategy in TRZ-induced cardiotoxicity.

Retraction: Longitude variation of the microRNA-497/FGF-23 axis during treatment and its linkage with neoadjuvant/adjuvant trastuzumab-induced cardiotoxicity in HER2-positive breast cancer patients.

[This retracts the article DOI: 10.3389/fsurg.2022.862617.].

Vagus nerve stimulation and acetylcholinesterase inhibitor donepezil provide cardioprotection against trastuzumab-induced cardiotoxicity in rats by attenuating mitochondrial dysfunction

Trastuzumab (Trz) is a targeted anticancer drug for human epidermal growth factor receptor 2 (HER2)-positive tumors, as Trz-induced cardiotoxicity (TIC) is commonly observed in Trz-treated patients. Since cardiac autonomic modulation with electrical vagus nerve stimulation (VNS) and acetylcholinesterase (AChE) inhibitors exerts cardioprotection against various heart diseases, the comparative effects of electrical VNS and an AChE inhibitor (donepezil) on cardiac and mitochondrial functions and programmed cell death pathways in TIC are not known. VNS devices were implanted in thirty-two male Wistar rats and were divided into 4 groups: (i) Control-Sham (CSham), (ii) Trz-Sham (TSham), (iii) Trz-VNS (TVNS), and (iv) Trz-donepezil (TDPZ). Rats in the Trz-treated groups were intraperitoneally injected with Trz (4 mg/kg/day) for 7 days, while CSham rats were injected with NSS. VNS devices were activated in the TVNS rats during the 7-day Trz treatment, but not in the sham rats. Rats in the TDPZ group received donepezil orally (5 mg/kg/day) for 7 days. At the end, left ventricular (LV) function and heart rate variability were evaluated, and heart tissue was collected for biochemical and histological analysis. Trz rats showed LV dysfunction and cardiac sympathovagal imbalance. In addition, mitochondrial function and dynamics were impaired in TIC rats. Trz also increased cardiomyocyte death by inducing apoptosis, pyroptosis, and ferroptosis. Electrical VNS and donepezil had similar efficacy in alleviating cardiac mitochondrial dysfunction, dynamic imbalances, and cardiomyocyte death, leading to improved LV function. These findings suggested that parasympathetic activation via either VNS or an AChE inhibitor could be a promising therapeutic intervention against TIC.

Acetylcholinesterase inhibition protects against trastuzumab-induced cardiotoxicity through reducing multiple programmed cell death pathways

BackgroundTrastuzumab (Trz)-induced cardiotoxicity (TIC) is one of the most common adverse effects of targeted anticancer agents. Although oxidative stress, inflammation, mitochondrial dysfunction, apoptosis, and ferroptosis have been identified as potential mechanisms underlying TIC, the roles of pyroptosis and necroptosis under TIC have never been investigated. It has been shown that inhibition of acetylcholinesterase function by using donepezil exerts protective effects in various heart diseases. However, it remains unknown whether donepezil exerts anti-cardiotoxic effects in rats with TIC. We hypothesized that donepezil reduces mitochondrial dysfunction, inflammation, oxidative stress, and cardiomyocyte death, leading to improved left ventricular (LV) function in rats with TIC.MethodsMale Wistar rats were randomly assigned to be Control or Trz groups (Trz 4 mg/kg/day, 7 days, I.P.). Rats in Trz groups were assigned to be co-treated with either drinking water (Trz group) or donepezil 5 mg/kg/day (Trz + DPZ group) via oral gavage for 7 days. Cardiac function, heart rate variability (HRV), and biochemical parameters were evaluated.ResultsTrz-treated rats had impaired LV function, HRV, mitochondrial function, and increased inflammation and oxidative stress, leading to apoptosis, ferroptosis, and pyroptosis. Donepezil co-treatment effectively decreased those adverse effects of TIC, resulting in improved LV function. An in vitro study revealed that the cytoprotective effects of donepezil were abolished by a muscarinic acetylcholine receptor (mAChR) antagonist.ConclusionsDonepezil exerted cardioprotection against TIC via attenuating mitochondrial dysfunction, oxidative stress, inflammation, and cardiomyocyte death, leading to improved LV function through mAChR activation. This suggests that donepezil could be a novel intervention strategy in TIC.

Late-onset cardiotoxicity in patients with HER2-positive metastatic breast cancer receiving trastuzumab-based therapy.

Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) typically receive long-term trastuzumab treatment for several years. The aim of our study is to identify the incidence and characterize late-onset cardiotoxicity in patients with HER2-positive MBC receiving trastuzumab-based therapy. We retrospectively reviewed charts of HER2-positive MBC patients who received >1 year of trastuzumab-based therapy at the Massachusetts General Hospital Cancer Center over three-year period. The primary endpoint was development of trastuzumab-induced cardiotoxicity (TIC). Secondary endpoints included time to TIC development, incidence/duration of trastuzumab interruption due to TIC, incidence of permanent discontinuation of trastuzumab due to TIC, clinic visit, or hospitalization due to TIC. Thirty-seven patients were included. Mean age was 56 years (range: 33-78 years, SD 9.5). Seven patients received prior doxorubicin and 14 patients received previous or concurrent breast irradiation. Mean duration of trastuzumab-based therapy was 57 months (range: 14-140 months, SD 39.3). Seven patients (18.9%) experienced TIC resulting in treatment interruption for two patients (28 and 78 days). The median time from starting trastuzumab therapy to TIC was 14 months (interquartile range: 11-29.5 months). The mean number of left ventricular ejection fraction (LVEF) assessment completed per year was 2.7 (range: 1.2-6.6, SD 1.1). Cardiotoxicity occurred in a minority of patients with HER2-positive MBC receiving trastuzumab-based therapy for more than one year. LVEF reductions to below the institutional lower limit of normal and therapy modifications were uncommon.

Acetylcholine receptor agonists effectively attenuated multiple program cell death pathways and improved left ventricular function in trastuzumab-induced cardiotoxicity in rats

AimsCardiotoxicity is a seriously debilitating complication of trastuzumab (TRZ) therapy in patients with cancer as a consequence of overexpression of the human epidermal growth factor receptor 2. Although most TRZ-induced cardiotoxicity (TIC) cases are reversible, some patients experience chronic cardiac dysfunction, and these irreversible concepts may be associated with cardiomyocyte death. Acetylcholine receptor (AChR) activation has been shown to exert cardioprotection in several heart diseases, but the effects of AChR agonists against TIC have not been investigated. Main methodForty adult male Wistar rats were randomized into 5 groups: (i) CON (0.9 % normal saline), (ii) TRZ (4 mg/kg/day), (iii) TRZ + α7nAChR agonist (PNU-282987: 3 mg/kg/day), (iv) TRZ + mAChR agonists (bethanechol: 12 mg/kg/day), and (v) TRZ + combined treatment (Combined PNU-282987 and bethanechol). Key findingsThe progression of TIC was driven by mitochondrial dysfunction, autophagic deficiency, and excessive myocyte death including by pyroptosis, ferroptosis, and apoptosis, which were significantly alleviated by α7nAChR and mAChR agonists. Interestingly, necroptosis was not associated with development of TIC. More importantly, the in vitro study validated the cytoprotective effects of AChR activation in TRZ-treated H9c2 cells, while not interfering with the anticancer properties of TRZ. All of these findings indicated that TRZ induced mitochondrial dysfunction, autophagic deficiency, and excessive myocyte death including pyroptosis, ferroptosis, and apoptosis, leading to impaired cardiac function. These pathological alterations were attenuated by α7nAChR and mAChR agonists. Significanceα7nAChR and mAChR agonists might be used as a future therapeutic target in the mitigation of TIC.

Trastuzumab-induced cardiotoxicity in breast cancer patients: A meta-analysis and review of the literature (2012-2022).

e24101 Background: Breast cancer (BC) is the most common type of cancer diagnosed, and 10-15% of BC patients develop a HER2-positive disease with a poor prognosis. In a previous meta-analysis of NCCTG N9831 and NSABP B-31 trials, treatment of early-stage HER2-positive BC patients with Trastuzumab and chemotherapeutic drugs improved overall survival by 37%. Trastuzumab-induced cardiotoxicity (TIC) is characterized by cardiac dysfunction, including decreased left ventricular ejection fraction (LVEF) and heart failure. Per package inserts, the incidence of TIC is 4-6 times higher than the control. An important risk factor for TIC is the administration of concomitant anthracycline chemotherapy. Several studies have reported that this treatment combination can significantly reduce LVEF compared to Trastuzumab alone. In this study, we compiled recent randomized controlled trials (RCTs) and clinical trial data to evaluate the incidence of cardiotoxicity in Trastuzumab-treated BC and study management guidelines specifically directed for TIC. This will help reduce the morbidity and mortality in these patients. Methods: Our search included PubMed, EMBASE, Web of Science, and Cochrane Library articles from July 2012 through July 2022. RCTs and clinical trials that used Trastuzumab as a therapy and reported its cardiotoxic effects were included. A random-effects model was utilized with Review Manager, and a P value &lt; 0.05 was considered significant. The entire analysis of treatment and control groups had various guideline-directed chemotherapies, including anthracycline-based regimens. Results: Our initial search yielded 26 results. After a full literature review by two independent reviewers, we selected four studies that included 1481 patients with cardiotoxicity data in the treatment and control groups. The analysis pooled from clinical trials showed that the odds of cardiotoxicity (specifically LVEF reduction) in patients treated with Trastuzumab were about seven times higher than the control group (OR 6.78, 95% CI 2.85-16.09, p-value &lt; 0.0001). The guidelines recommend withholding Trastuzumab for ≥ 16% absolute decrease in LVEF from pre-treatment values or an LVEF value below normal institutional limits and ≥ 10% absolute decrease in LVEF from pretreatment values. The safety of continuation or resumption of Trastuzumab in patients with TIC has not been studied, and there are no standardized management guidelines. Conclusions: We conclude in our study that the odds of TIC are increased by almost seven times compared to chemotherapy alone. In addition to just regular monitoring of these patients with history, physical examination, and determination of LVEF by echocardiogram or MUGA scan per protocol, there is a need to formulate guidelines for continuation or resumption of Trastuzumab in patients with TIC.

Comparative Evaluation of Biosimilar Trastuzumab with Reference Trastuzumab Activity in HER2-Positive Breast Cancer Patients.

One of the breast cancer subtypes, epidermal growth factor receptor 2 (HER2), accounts for 15% of all breast cancers and is characterized by aggressive behavior and a poor prognosis. For patients with HER2-positive breast cancer, trastuzumab, a monoclonal antibody that targets HER2 receptors, is prescribed in addition to chemotherapy to increase their chances of survival. However, the high expense of this treatment makes it impossible for patients in developing nations to easily afford it and undergo this biological therapy. Consequently, trastuzumab biosimilars have been launched as a substitute that offers comparable effectiveness at a reduced price. This study aimed to compare the biological activity and cardiac safety of reference trastuzumab with biosimilar trastuzumab by monitoring serum levels of the tumor biomarker CA15-3 and evaluating N-terminal pro-B-type natriuretic peptide (NT-proBNP) for the adverse cardiac effects of both treatments on HER2-positive breast cancer patients before and after six cycles of biological therapy. This prospective research was performed on 36 females with metastatic and early-stage HER2-positive breast cancer who visited the Oncology Department at Rizgary Hospital, Erbil, Iraq. The patients were within the age range of 30-80 years old. Eighteen individuals received reference trastuzumab, while the remaining 18 received both chemotherapy and biosimilar trastuzumab. Each patient had a data sheet that contained details from hospital-reserved files. In the Herceptin group, there was an insignificant difference in the median of CA15-3, while no significant difference was detected between the means of NT-proBNP before and after treatment. In the biosimilar group, there was a significant reduction in the median CA15-3 as well as a significant increase in the level of NT-proBNP before and after the treatment. Evaluation of the association of trastuzumab-induced cardiotoxicity during breast cancer treatment with different factors indicated that there might be an increased risk of cardiotoxicity after trastuzumab treatment.